Essential role of DAP12 signaling in macrophage programming into a fusion-competent state.
Multinucleated giant cells, formed by fusion of macrophages, are a hallmark of granulomatous inflammation. With a genetic approach, we show that signaling through the adaptor protein DAP12 (DNAX activating protein of 12 kD), its associated receptor triggering receptor expressed by myeloid cells 2 (TREM-2), and the downstream protein tyrosine kinase Syk is required for the cytokine-induced formation of giant cells and that overexpression of DAP12 potentiates macrophage fusion. We also present evidence that DAP12 is a general macrophage fusion regulator and is involved in modulating the expression of several macrophage-associated genes, including those encoding known mediators of macrophage fusion, such as DC-STAMP and Cadherin 1. Thus, DAP12 is involved in programming of macrophages through the regulation of gene and protein expression to induce a fusion-competent state.
Helming
Laura
L
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Tomasello
Elena
E
Kyriakides
Themis R
TR
Martinez
Fernando O
FO
Takai
Toshiyuki
T
Gordon
Siamon
S
Vivier
Eric
E
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002459:Cell Fusion; D016207:Cytokines / Q000494:pharmacology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008264:Macrophages / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics*; D000072377:Syk Kinase
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; C484963:Tyrobp protein, mouse; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse